Studies of Lymphocyte Kinetics Using Stable Isotopes

Purpose:

This study will examine how quickly white blood cells called CD4 lymphocytes replicate
(divide) and how long they live in both HIV-infected and non-infected people by measuring how
quickly the genetic material (DNA) of cells is replicated. To do this, participants will
receive infusions of glucose, a non-radioactive form of a type of sugar. Cells normally use
glucose to make various products needed for cell growth and replication, including cell DNA.
Measuring how much glucose cells incorporate into their DNA can provide important information
about cell replication. This rate of incorporation will be examined and compared in
HIV-infected people and in healthy, normal volunteers.
HIV-infected patients and non-infected healthy volunteers 18 years of age and older may be
eligible for this study. Candidates will be screened with a medical history, physical
examination, chest X-ray, electrocardiogram (EKG) and blood tests.
Participants will be given a continuous infusion of glucose at a dose of up to 60 grams
(about 2 ounces) per day for up to 5 days. The glucose will be delivered through a catheter
(thin plastic tube) placed in an arm vein. Blood samples will be collected as often as daily
in the first week following the infusion and then from twice a week to once a month for up to
4 years. Alternatively, patients may undergo leukapheresis a procedure for collecting
quantities of lymphocytes up to 10 times during the first month after the infusion, and
possibly later as well, but no more often than once every 2 weeks. For this procedure, whole
blood is collected through a needle in an arm vein. The blood circulates through a machine
that separates it into its components. The white cells are removed and the rest of the blood
is returned to the body either through the same needle or through a second needle in the
other arm. Participants may be asked to receive up to four glucose infusions. There will be
at least a 2-week interval between infusions. Participants who have more than three
leukapheresis procedures within 3 weeks will have at least 6 weeks between infusions.
Participants will be followed periodically in the outpatient clinic for evaluation and tests.
This study may provide a better understanding of how HIV causes disease and progressive
weakening of the immune system and how therapies affect immunity.

Study summary:

Understanding the rate of lymphocyte replication and destruction in HIV-infected patients, as
well as the effects of therapy on lymphocyte replication should lead to a better
understanding of the mechanisms behind the immunodeficiency induced by HIV. To examine this
directly, up to 100 HIV-infected patients will receive up to 5 days of continuous infusions
with [6,6-(2)H(2)]-glucose, a nonradioactive, stable isotope of glucose that is safe to
administer. The deuterium is incorporated into DNA via metabolism of glucose to ribose and
incorporation into nucleotides. The rate of incorporation can be measured in subpopulations
of cells to determine the rate of replication of those cells. Fifty HIV-uninfected persons
will also be enrolled in the protocol to allow a determination of lymphocyte kinetics in
individuals with normally functioning immune systems or immune systems that may have been
affected by other diseases. All participants in this study will be reimbursed for the
inconvenience and discomfort associated with study participation.

Criteria:

- INCLUSION CRITERIA:
FOR PATIENTS:
18 years or older.
Able to provide informed consent and willing to comply with study requirements and clinic
policies.
Negative urine pregnancy test (for women of childbearing potential).
Hemoglobin greater than 10 mg/dl.
Adequate venous access in the arms for blood drawing and 5 day infusions, and
lymphapheresis
Willingness to allow stored samples to be used for future studies of HIV infection and/or
immunological function, and willingness to have HLA typing performed. (For previously
enrolled patients, patients would be requested, but not required, to provide permission to
use stored samples in the future, and to permit HLA testing
FOR HIV POSITIVE PATIENTS:
Documented HIV infection (ELISA/Western blot positive or, for acute seroconverters, PCR
positive).
FOR HIV NEGATIVE PATIENTS:
Negative ELISA/Western blot.
EXCLUSION CRITERIA:
Diabetes mellitus requiring drug therapy.
Active substance abuse or prior history of substance abuse which may interfere with
protocol compliance.
Psychiatric illness or disturbance which, in the assessment of the protocol team, may
affect patient safety or compliance.
Significant underlying cardiac, pulmonary, renal, gastrointestinal, rheumatologic or CNS
disease as detectable on routine history, physical exam, or screening laboratory studies.
Patients would be excluded if they had an acute or chronic underlying medical problem that
in the judgment of the principal investigator could be exacerbated by participating in the
protocol or that would make it difficult for them to comply with the protocol requirements.
Pregnancy or breast-feeding.